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* From the Department of Pediatrics (Drs. Lothian and Grey), Department of Biochemistry (Dr. Grey), and Division of Respiratory Medicine (Dr. Lands), McGill University Health Centre–Montreal Children’s Hospital, Montreal, Quebec, Canada; and Division of Respiratory Medicine (Dr. Kimoff), McGill University Health Centre–Royal Victoria Hospital, Montreal, Quebec, Canada.
Correspondence to: Larry C. Lands, MD, PhD, Assistant Director, Respiratory Medicine, The Montreal Children’s Hospital, Room D-380, 2300 Tupper St, Montreal, Quebec, Canada H3H 1P3; e-mail: larry.lands{at}muhc.mcgill.ca
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Abstract |
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Key Words: glutathione • inflammation • oxidative stress • supplementation
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Introduction |
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Case Report |
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She returned 2 weeks later (time 4) with significant symptomatic improvement while still taking systemic corticosteroids and regular bronchodilators (salbutamol metered-dose inhaler and ipratropium bromide metered-dose inhaler qid). An attempt was made to discontinue prednisone. When the patient was seen 1 month later (time 5), her symptoms had returned. At that time, review of her history revealed no environmental insult that could account for her deterioration. Additionally, serum IgE was 52 kU/L (laboratory control, 0 to 100 kU/L), and both allergen skin testing and Aspergillus precipitins testing were negative. A further course of oral prednisone was prescribed (40 mg/d initially; tapering over 1 month).
Four months later (time 6), the patient returned to clinic independently, having begun taking HMS90 (Immunocal; Immunotec Research Ltd; Vaudreuil, Quebec, Canada), a whey-based protein supplement (10 g bid), 1 month before. She had heard that the product could be helpful in inflammatory conditions, and had started taking the product of her own accord. She reported a remarkable improvement in her respiratory status and had discontinued all inhalers and steroids, and was not taking any other supplements, medications, or over-the-counter therapies. She was asked to discontinue the Immunocal, and within 3 months her symptoms returned. PFTs were performed at this time (time 7). She then restarted Immunocal of her own accord, and 1 month later (time 8), PFTs were again assessed. Additionally, whole blood GSH levels were measured before and 1 month after therapy was reinitiated, using a modification of the method previously described.6 7 Again, a remarkable improvement in both symptoms and PFTs was noted (Fig 1) . In addition, the total lung capacity increased from 3.91 L at time 7 to 5.00 L at time 8, and the residual volume/total lung capacity ratio fell from 33 to 28%. Her whole blood GSH levels increased from 235 to 457 µmol/L (laboratory control, 589.2 ± 112.6 µmol/L; n = 10). It should be further remarked that the last two PFTs performed showed reversibility of the obstructive airway disease (change in FEV1, 48% at time 7 to 15% at time 8), whereas no prior PFT had shown reversibility. The patient continues to take HMS90 and no other respiratory medications, without return of her symptoms.
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Discussion |
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HMS90 is a bovine whey-protein concentrate purified by ultrafiltration
and low-temperature pasteurization of milk. The undenatured whey
protein is rich in cystine (the oxidized form of cysteine) and
-glutamylcystine,6
which are precursors of GSH
synthesis. The tripeptide GSH (glycyl--glutamylcysteine) is
synthesized in the cell in two steps. The first step, the synthesis of
-glutamylcysteine, is limited by the availability of intracellular
cysteine.4
As well, -glutamylcysteine, as a
-glutamyl amino acid, can easily be transported into the cell where
it combines with glycine in the second step of GSH
synthesis.8
Cells cannot take up extracellular
GSH.3
In the patient described, whole blood GSH levels were significantly increased (94%) following regular intake of HMS90. This is much higher than the reported intraindividual variation in whole blood GSH values (7.8 to 15.8%).9 In order to avoid any possible influence of the timing of sampling on GSH levels and pulmonary function, the patient was tested between 10:00 AM and 11:00 AM on each visit. Animal studies of GSH metabolism have demonstrated that whole blood GSH is reflective, temporally and quantitatively, of lymphocyte and tissue GSH levels. Although no direct markers of oxidant/antioxidant status or inflammation were measured in the patient described, the observed clinical effect is coincident with augmented GSH levels.
Several specific abnormalities, or inadequacies, of the GSH antioxidant system have been identified in reversible obstructive airway disease. GSH itself is present in high concentrations in the lung epithelial lining fluid (ELF), where it may act to directly reduce ROS.10 11 Clinically stable asthmatics have higher ELF GSH than symptomatic asthmatics,5 while experimental models of oxidative stress show an increase in ELF GSH with oxidative stress.10 Upregulation of antioxidant defenses, although not in proportion to oxidative stress, is hypothesized to account for the increased BAL fluid GSH levels observed in both these studies and other pulmonary conditions that are attributed, in part, to excessive oxidative stress.10 GSH is also a substrate for the enzyme glutathione peroxidase (GSH-Px), which catalyzes the decomposition of a large number of ROSs (including hydrogen and other peroxidases).4 Studies have shown decreased peripheral blood GSH-Px activity in asthmatic patients.1 Finally, it has been recently demonstrated in a murine model that GSH levels in the antigen presenting cell affect the differentiation of the T-helper cell Th1/Th2 cytokine response.12
Improvement in GSH status could result in augmented lung function
through several mechanisms. Within lung epithelial cells, augmented GSH
may block the activation of nuclear factor 
B by tumor necrosis
factor-
,13
14
15
and so limit the production and release
of proinflammatory cytokines. Augmented intracellular GSH may reduce
the need to recycle GSH from the lung lining fluid, and thus maintain
extracellular levels.16
Alternatively, increased
intracellular GSH levels may lead to extracellular transport to
buttress lung lining levels. In the lung lining fluid, augmented GSH
may prevent oxidative damage to antiproteases.17
18
Improvement in skeletal muscle function due to augmented GSH
stores7
may also partially account for our results, as the
baseline FEV1/FVC ratio did not change between
times 7 and 8 (66% and 62%, respectively).
The ELF GSH pool has been the target of direct administration of nebulized GSH, although success has been limited by GSH-induced bronchospasm.5 Trials of systemic N-acetyl cysteine, acting as both a cysteine donor and an ROS scavenger, for the treatment of chronic obstructive airway disease have met with limited success, because of N-acetyl cysteine toxicity and limited clinical effect.2 19
The relationship between whole blood GSH, lung epithelial cell GSH levels, ELF GSH, and peripheral blood GSH-Px activity is poorly defined. There are several possible mechanisms by which GSH could improve obstructive airway disease, either via immunologic modulation or by improving antioxidant defenses. More work needs to be done to further define the specific abnormalities of antioxidant function, as well as the relative contribution of such abnormalities to the pathophysiology observed in obstructive airway disease. Nevertheless, the modulation of GSH and antioxidant defenses in obstructive airway disease (and many other diseases) represents an intriguing potential modality for anti-inflammatory therapy.
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Footnotes |
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L.C. Lands and R.J. Kimoff are clinical investigators with the Fonds de la Recherche en Santé du Québec.
Received for publication June 21, 1999. Accepted for publication September 14, 1999.
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